Specific recurring cytogenetic and molecular abnormalities include:
t(8;21): In leukemias with t(8;21), the AML1 (RUNX1, CBFA2) gene on chromosome 21 is fused with the ETO gene on chromosome 8. The t(8;21) translocation is associated with the FAB M2 subtype and with granulocytic sarcomas.[32,33] Adults with t(8;21) have a more favorable prognosis than adults with other types of AML.[25,34] Several reports describe a more favorable outcome for children with t(8;21) AML compared with children with AML characterized by normal or complex karyotypes.[25,35,36,37]
inv(16): In leukemias with inv(16), the CBF beta gene at chromosome band 16q22 is fused with the MYH11 gene at chromosome band 16p13. The inv(16) translocation is associated with the FAB M4Eo subtype. Inv(16) confers a favorable prognosis for both adults and children with AML.[25,35,36,37]
t(15;17): AML with t(15;17) is invariably associated with APL, a distinct subtype of AML that is treated differently than other types of AML because of its marked sensitivity to the differentiating effects of all-trans retinoic acid. The t(15;17) translocation leads to the production of a fusion protein involving the retinoid acid receptor alpha and PML. Other much less common translocations involving the retinoic acid receptor alpha can also result in APL (e.g., t[11;17] involving the PLZF gene). Identification of cases with the t(11;17) is important because of their decreased sensitivity to all-trans retinoic acid.[39,40]
MLL gene rearrangements: Translocations of chromosomal band 11q23 involving the MLL gene, including most AML secondary to epipodophyllotoxin, are associated with monocytic differentiation (FAB M4 and M5). The most common translocation, representing approximately 50% of MLL-rearranged cases in the pediatric AML population, is t(9;11)(p22;q23) in which the MLL gene is fused with the AF9 gene. However, more than 50 different fusion partners have been identified for the MLL gene in patients with AML. The median age for 11q23/MLL-rearranged cases in the pediatric AML setting is approximately 2 years and most translocation subgroups have a median age at presentation of less than 5 years. However, pediatric cases with t(6;11)(q27;q23) and t(11;17)(q23;q21) have significantly older median ages at presentation (12 years and 9 years, respectively).
Outcome for patients with de novo AML and MLL gene rearrangement are generally reported as being similar to that for other patients with AML.[25,42,43] However, as the MLL gene can participate in translocations with many different fusion partners, the specific fusion partner appears to influence prognosis as demonstrated by a large international retrospective study evaluating outcome for 756 children with 11q23- or MLL-rearranged AML. For example, cases with t(1;11)(q21;q23), representing 3% of all 11q23/MLL-rearranged AML, showed a highly favorable outcome with 5-year event-free survival (EFS) of 92%. While several reports have described more favorable prognosis for cases with t(9;11), in which the MLL gene is fused with the AF9 gene, the international retrospective study did not confirm the favorable prognosis of the t(9;11)(p22;q23) subgroup.[25,42,44,45,46] A similarly inferior outcome for patients with t(9;11) AML was reported from the AML-BFM 98 study.
Several 11q23/MLL-rearranged AML subgroups are associated with poor outcome. For example, cases with the t(10;11) translocation are a group at particularly high risk of relapse in bone marrow and the central nervous system (CNS).[25,47] Some cases with the t(10;11) translocation have fusion of the MLL gene with the AF10/MLLT10 at 10p12, while others have fusion of MLL with ABI1 at 10p11.2.[48,49] The international retrospective study found that these cases, which present at a median age of approximately 1 year, have a 5-year EFS in the 20% to 30% range. Patients with t(6;11)(q27;q23) and with t(4;11)(q21;q23) also show poor outcome, with a 5-year EFS of 11% and 29%, respectively.
t(6;9): t(6;9) leads to the formation of a leukemia-associated fusion protein DEK-NUP214. This subgroup of AML has been associated with a poor prognosis.[50,51,52]
Abnormalities with chromosomes 3, 5, and 7: Chromosomal abnormalities associated with poor prognosis in adults with AML include those involving chromosome 7 (monosomy 7), chromosome 5 (monosomy 5 and del[5q]), and the long arm of chromosome 3 (inv[q21;q26] or t[3;3][q21;q26]).[25,34] These cytogenetic subgroups are also associated with poor prognosis in children with AML, though abnormalities of the long arm of chromosomes 3 and 5 are extremely rare in pediatric patients.[34,53,54] In the past, patients with del(7q) were also considered to be at high risk of treatment failure. However, subsequent reports indicate that outcome for both adults and children with del(7q), but not monosomy 7, are comparable to that of other patients with AML. The presence of del(7q) does not abrogate the prognostic significance of favorable cytogenetic characteristics (e.g., inv, t[8;21]).[25,55,56]
t(1;22): The t(1;22)(p13;q13) translocation is restricted to AMKL and occurs in as many as one-third of AMKL cases in children.[57,58,59] Most AMKL cases with t(1;22) occur in infants, and the translocation is uncommon in children with Down syndrome who develop AMKL.[57,59] In leukemias with t(1;22), the OTT (RBM15) gene on chromosome 1 is fused to the MAL (MLK1) gene on chromosome 22.[60,61] Cases with detectable OTT/MAL fusion transcripts in the absence of t(1;22) have been reported, as well. In the small number of children reported, the presence of the t(1;22) appears to be associated with poor prognosis, though long-term survivors have been noted following intensive therapy.[59,62]
12p abnormalities: The presence of 12p abnormalities has been reported to be associated with a significantly worse prognosis.[28,29]
FLT3 mutations: Presence of a FLT3 internal-tandem duplication (ITD) mutation appears to be associated with poor prognosis in adults with AML, particularly when both alleles are mutated or there is a high ratio of the mutant allele to the normal allele.[64,65]FLT3-ITD mutations also convey a poor prognosis in children with AML.[66,67,68,69,70] The frequency of FLT3-ITD mutations in children is lower than that observed in adults, especially for children younger than 10 years, for whom 5% to 10% of cases have the mutation (compared with approximately 30% for adults).[68,69,71] A longer length of the ITD segment of FLT3-ITD has been reported to be associated with a poorer outcome.
Activating point mutations of FLT3 have also been identified in both adults and children with AML,[64,68,73] though the clinical significance of these mutations is not clearly defined. FLT3-ITD and point mutations occur in 30% to 40% of children and adults with APL.[67,74,75,76] Presence of the FLT3-ITD mutation is strongly associated with the microgranular variant (M3v) of APL and with hyperleukocytosis.[67,76] It remains unclear whether FLT3 mutations are associated with poorer prognosis in patients with APL who are treated with modern therapy that includes all-trans retinoic acid.[74,75]
RAS and other tyrosine kinase receptor mutations (e.g., c-KIT): Although mutations in RAS have been identified in approximately 25% of patients with AML, the prognostic significance has not been clearly shown.[77,78] A report in adults has suggested that AML characterized by RAS mutations has increased sensitivity to cytarabine and benefits more from higher cytarabine doses than does wild-type RAS. Mutations in c-KIT occur in less than 5% of AML, but in 10% to 40% of AML with core-binding factor abnormalities.[80,81] The presence of activating c-KIT mutations in adults with this subgroup of AML appears to be associated with a poorer prognosis compared with core-binding factor AML without c-KIT mutation.[81,82,83] The prognostic significance of c-KIT mutations occurring in pediatric core-binding factor AML remains unclear.[80,84,85,86]
GATA1 mutations: GATA1 mutations are present in most, if not all, Down syndrome children with either transient myeloproliferative disease or AMKL.[87,88,89,90]GATA1 mutations are not observed in non-Down syndrome children with AMKL or in Down syndrome children with other types of leukemia.[89,90]GATA1 is a transcription factor that is required for normal development of erythroid cells, megakaryocytes, eosinophils, and mast cells.GATA1 mutations confer increased sensitivity to cytarabine by down-regulating cytidine deaminase expression, possibly providing an explanation for the superior outcome of children with Down syndrome and M7 AML when treated with cytarabine-containing regimens.
Nucleophosmin (NPM1) mutations: NPM1 is a protein that has been linked to ribosomal protein assembly and transport as well as being a molecular chaperone involved in preventing protein aggregation in the nucleolus. Immunohistochemical methods can be used to accurately identify patients with NPM1 mutations by the demonstration of cytoplasmic localization of NPM. Mutations in the NPM1 protein that diminish its nuclear localization are primarily associated with a subset of AML with a normal karyotype, absence of CD34 expression, and an improved prognosis in the absence of FLT3-ITD mutations in adults and younger adults.[94,95,96,97,98,99] Preliminary studies of children with AML suggest a lower rate of occurrence of this mutation in children compared with adults with normal cytogenetics.[100,94,95,96,97,101,102]NPM1 mutations have been reported to occur in approximately 8% of pediatric patients with AML and are associated with a favorable prognosis in patients with AML characterized by a normal karyotype. In this pediatric population, the presence of NPM1 mutations did not appear to completely abrogate the poor prognosis of having an FLT3-ITD mutation.
CEBPA mutations: Mutations in the CCAAT/Enhancer Binding Protein Alpha gene (CEBPA) occur in a subset of children and adults with cytogenetically normal AML. In adults younger than 60 years, approximately 15% of cytogenetically normal AML cases have mutations in CEBPA.[98,104] Outcome for adults with AML, with CEBPA mutations, appears to be relatively favorable and similar to that of patients with core binding factor leukemias.[98,104] Studies in adults with AML have demonstrated that CEBPA double-mutant, but not single allele mutant, AML was associated with a favorable prognosis.[105,106]CEBPA mutations occur in approximately 5% of children with AML and have been preferentially found in the cytogenetically normal subtype of AML; approximately 80% of pediatric patients have double mutant alleles and these mutations have been shown to predict a significantly improved survival, similar to adult studies. Although both double and single mutant alleles of CEBPA were associated with a favorable prognosis in children with AML in one large study, very low numbers of children with single allele mutants were included, making a conclusion that single allele CEBPA mutants confer a favorable prognosis in children premature.
WT1 mutations: WT1, a zinc-finger protein regulating gene transcription, is mutated in approximately 10% of cytogenetically normal cases of AML in adults.[108,109,110,111] The WT1 mutation has been shown in some,[108,109,111] but not all, studies to be an independent predictor of worse disease-free, event-free, and overall survival in adults. In children with AML, WT1 mutations are observed in approximately 10% of cases.[112,113] Cases with WT1 mutations are enriched among children with normal cytogenetics and FLT3-ITD, but are less common among children younger than 3 years.[112,113] In univariate analyses, WT1 mutations are predictive of poorer outcome in pediatric patients, but the independent prognostic significance of WT1 mutation status is unclear because of its strong association with FLT3-ITD.[112,113] The largest study of WT1 mutations in children with AML observed that children with WT1 mutations in the absence of FLT3-ITD had outcomes similar to that of children without WT1 mutations, while children with both WT1 mutation and FLT3-ITD had survival rates less than 20%.
DNMT3A mutations: Mutations of the DNA cytosine methyltransferase gene (DNMT3A) have been identified in approximately 20% of adult AML patients, being virtually absent in patients with favorable cytogenetics but occurring in one-third of adult patients with intermediate-risk cytogenetics. Mutations in this gene are independently associated with poor outcome.[114,115]DNMT3A mutations appear to be very uncommon in children.